11-126293229-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000392678.7(TIRAP):c.*112C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 1,232,986 control chromosomes in the GnomAD database, including 377,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (41951 hom., cov: 32)
  • Exomes 𝑓: 0.79 (335770 hom.)
• Consequence: TIRAP ENST00000392678.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.42

Genes affected

TIRAP (HGNC:17192): (TIR domain containing adaptor protein) The innate immune system recognizes microbial pathogens through Toll-like receptors (TLRs), which identify pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns and all TLRs have a Toll-interleukin 1 receptor (TIR) domain, which is responsible for signal transduction. The protein encoded by this gene is a TIR adaptor protein involved in the TLR4 signaling pathway of the immune system. It activates NF-kappa-B, MAPK1, MAPK3 and JNK, which then results in cytokine secretion and the inflammatory response. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-126293229-C-T is Benign according to our data. Variant chr11-126293229-C-T is described in ClinVar as [Benign]. Clinvar id is 2688397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.646+174C>T		intron_variant		ENST00000392679.6
TIRAP	NM_001039661.2	c.646+174C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.646+174C>T		intron_variant		2	NM_001318777.2	P1
	ENST00000533378.1	n.185G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111400 AN: 151928 Hom.: 41915 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.786 AC: 849810 AN: 1080940 Hom.: 335770 Cov.: 14 AF XY: 0.790 AC XY: 430528 AN XY: 544930

Gnomad4 AFR exome AF: 0.554

Gnomad4 AMR exome AF: 0.846

Gnomad4 ASJ exome AF: 0.758

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.881

Gnomad4 FIN exome AF: 0.779

Gnomad4 NFE exome AF: 0.775

Gnomad4 OTH exome AF: 0.779

GnomAD4 genome AF: 0.733 AC: 111489 AN: 152046 Hom.: 41951 Cov.: 32 AF XY: 0.743 AC XY: 55227 AN XY: 74304

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.802

Gnomad4 ASJ AF: 0.753

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.889

Gnomad4 FIN AF: 0.800

Gnomad4 NFE AF: 0.776

Gnomad4 OTH AF: 0.730

Alfa AF: 0.739 Hom.: 5741

Bravo AF: 0.723

Asia WGS AF: 0.926 AC: 3219 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 58% of patients studied by a panel of primary immunodeficiencies. Number of patients: 51. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.28
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs609634; hg19: chr11-126163124;